Abstract
Malaria is a major worldwide public health threat with worrying social and economic burdens due to the rapid emergence of multidrug-resistant Plasmodium falciparum strains. As a result, there is an urgent need to find novel drugs that might overcome clinical resistance to marketed antimalarials. In recent years, the mitochondrial electron transport chain (mtETC) has been explored for the development of new antimalarials. Type II NADH:quinone oxidoreductase (PfNDH2), succinate dehydrogenase (SDH) and cytochrome bc1 have become a major focus of those efforts, leading to several studies of its biochemistry and the design of potent inhibitors. Furthermore, de novo pyrimidine biosynthesis in malaria parasites, particularly dihydroorotate dehydrogenase (PfDHODH), is also receiving increasing attention. The enzymes involved in the mtETC are valuable targets in malaria chemotherapy, not only because they play a critical role in metabolic pathways of P. falciparum, but also because they differ significantly from the analogous mammalian system. Inhibition of such enzymes results in the shutdown of mitochondrial electron flow, leading to the arrest of pyrimidine biosynthesis and consequent parasite death. In this review, we aim to outline recent advances in the inhibition of mitochondrial metabolic pathways, highlighting the major classes of known inhibitors and those that are currently being developed.
Keywords: Malaria, electron transport chain, mitochondria, bc1 complex, dihydroorotate dehydrogenase, succinate dehydrogenase, type II NADH dehydrogenase
Current Medicinal Chemistry
Title: Inhibitors of the Mitochondrial Electron Transport Chain and de novo Pyrimidine Biosynthesis as Antimalarials: The Present Status
Volume: 17 Issue: 10
Author(s): T. Rodrigues, F. Lopes and R. Moreira
Affiliation:
Keywords: Malaria, electron transport chain, mitochondria, bc1 complex, dihydroorotate dehydrogenase, succinate dehydrogenase, type II NADH dehydrogenase
Abstract: Malaria is a major worldwide public health threat with worrying social and economic burdens due to the rapid emergence of multidrug-resistant Plasmodium falciparum strains. As a result, there is an urgent need to find novel drugs that might overcome clinical resistance to marketed antimalarials. In recent years, the mitochondrial electron transport chain (mtETC) has been explored for the development of new antimalarials. Type II NADH:quinone oxidoreductase (PfNDH2), succinate dehydrogenase (SDH) and cytochrome bc1 have become a major focus of those efforts, leading to several studies of its biochemistry and the design of potent inhibitors. Furthermore, de novo pyrimidine biosynthesis in malaria parasites, particularly dihydroorotate dehydrogenase (PfDHODH), is also receiving increasing attention. The enzymes involved in the mtETC are valuable targets in malaria chemotherapy, not only because they play a critical role in metabolic pathways of P. falciparum, but also because they differ significantly from the analogous mammalian system. Inhibition of such enzymes results in the shutdown of mitochondrial electron flow, leading to the arrest of pyrimidine biosynthesis and consequent parasite death. In this review, we aim to outline recent advances in the inhibition of mitochondrial metabolic pathways, highlighting the major classes of known inhibitors and those that are currently being developed.
Export Options
About this article
Cite this article as:
Rodrigues T., Lopes F. and Moreira R., Inhibitors of the Mitochondrial Electron Transport Chain and de novo Pyrimidine Biosynthesis as Antimalarials: The Present Status, Current Medicinal Chemistry 2010; 17 (10) . https://dx.doi.org/10.2174/092986710790820660
DOI https://dx.doi.org/10.2174/092986710790820660 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Chloride Channels − New Targets for the Prevention of Stroke
Current Vascular Pharmacology Blocking Leukocyte Rolling: Does it have a Role in Disease Prevention?
Vascular Disease Prevention (Discontinued) The Protective Effects of Silymarin on the Reproductive Toxicity: A Comprehensive Review
Current Medicinal Chemistry Moderate Hypothermia in the Management of Severe Traumatic Brain Injury: A Good Idea Proved Ineffective?
Current Pharmaceutical Design Encephalopathy: A Vicious Cascade Following Forebrain Ischemia and Hypoxia
Central Nervous System Agents in Medicinal Chemistry Microbial / Enzymatic Synthesis of Chiral Intermediates for Pharmaceuticals: Case Studies from BMS
Current Organic Chemistry ATP Citrate Lyase Inhibitors as Novel Cancer Therapeutic Agents
Recent Patents on Anti-Cancer Drug Discovery Wasp Venom Toxins as a Potential Therapeutic Agent
Protein & Peptide Letters Drugs and Rhabdomyolysis: From Liver to Kidney
Current Vascular Pharmacology The Role of Statins in Preventing the Progression of Congestive Heart Failure in Patients with Metabolic Syndrome
Current Pharmaceutical Design Role of Hexokinase and VDAC in Neurological Disorders
Current Molecular Pharmacology Biochemical Markers of Renal Function
Current Medicinal Chemistry Mitochondrial Functionality and Chemical Compound Action on Sperm Function
Current Medicinal Chemistry Drug-Induced Peripheral Neuropathy: Diagnosis and Management
Current Cancer Drug Targets Oleic Acid in Olive Oil: From a Metabolic Framework Toward a Clinical Perspective
Current Pharmaceutical Design Significance of Aspirin and Clopidogrel Resistance in Patients Undergoing Percutaneous Coronary Interventions
Current Vascular Pharmacology <i>Momordica balsamina L</i>.: An Appraisal on Morphology, Ecological Diversity, Phytochemistry, Pharmacological and Biotechnological Applications
Current Traditional Medicine Molecular Treatment of Different Breast Cancers
Anti-Cancer Agents in Medicinal Chemistry Engineering Three-Dimensional Cardiac Microtissues for Potential Drug Screening Applications
Current Medicinal Chemistry Does Glucagon-like Peptide-1 Ameliorate Oxidative Stress in Diabetes? Evidence Based on Experimental and Clinical Studies
Current Diabetes Reviews